The leading causes of irreversible blindness include age-related macular degeneration (AMD), retinitis pigmentosa, glaucoma, and retinal vascular diseases, which cause loss of RPE, photoreceptors, retinal ganglion cells (RGCs), and supporting cells in the retina. One potential therapeutic approach is to restore visual function by grafting healthy retinal cells to replace the lost retinal cells. During the past several decades, attempts at using primary retinal progenitor cells isolated from human fetal or adult retinal tissues have met with limited success1, either due to the low expansion capacity and differentiation potential of adult progenitors or the difficulty of obtaining sufficient human fetal retinal progenitors, raising ethical concerns. Human pluripotent stem cells (hPSCs), including human embryonic stem cells (hESCs), and induced pluripotent stem cells (iPSCs) represent promising renewable donor sources for cell-based replacement therapy. Nevertheless, hPSCs themselves are not suitable for direct transplantation in clinical applications due to their tendency to form teratomas and their low efficiency in repopulating host tissues with desirable reprogrammed cell types in vivo.
Thus, major efforts have focused on production of differentiated derivatives of hPSCs such as neural retinal progenitor cells2,3, retinal pigment epithelium (RPE)4-6, and photoreceptors7-9. While hESC-derived RPE transplants have now advanced to clinical trials for treatment of patients with Stargardt's macular dystrophy and AMD10, the effectiveness of RPE grafts may be limited if the majority of photoreceptors have already been lost. Thus, it is highly desirable to develop a renewable retinal stem cell product with the potential to repopulate both RPE and photoreceptors in degenerated retina, yet that poses no risk of forming tumors. Such a product would replace damaged cells and restore visual circuits in conditions where multiple cell types are afflicted.